A recently developed system capable of detecting mutation to 8 azaguanine (AG) resistance in cultured, diploid human fibroblasts is being exploited to quantitatively assess x-ray induced mutation in human cells. The system is also being used to study chemical agents potentially mutagenic to human genetic material. System improvements are being made to allow detection of low order mutagenesis. Derived mutant clones are being studied with reference to mechanisms of purine analogue resistance at the single cell level. The system may also have utility as a screening test for environmental carcinogens. A viral plaque system capable of detecting infrequent AG resistant lymphocytes in blood is being developed as a direct assay for human somatic cell mutation arising in vivo. Normal values for AG resistant lymphocytes will be established and patients receiving various drugs will be monitored for changes in this frequency. Correlations between in vitro and in vivo mutagenicity of agents will be made and the relative mutability of lymphocytes vs. fibroblasts determined. The lymphocyte system will also be used to monitor patients on long term purine analogue chemotherapy, and may provide a rational basis for later development of sequential chemotherapy programs. AG resistant lymphocytes will be used to identify females heterozygous for mutations of the X-linked gene for hypoxanthine-guanine phosphoribosyltransferase and selection, in vivo, against cells mutant for this gene will be studied.